tbuckley/cabot-search huggingface dataset:
Protein Kinase B (PKB/AKT) Protects IDH-Mutated Glioma from Ferroptosis via Nrf2
Authors: Yang Liu, Fu-Ju Chou, Fengchao Lang, Meili Zhang, Hua Song, Wei Zhang, Dionne L. Davis, Nicole J. Briceno, Yang Zhang, Patrick J. Cimino, Kareem A. Zaghloul, Mark R. Gilbert, Terri S. Armstrong, Chunzhang Yang
Journal: Clinical Cancer Research (2023)

Mutations of the isocitrate dehydrogenase (IDH) gene are common genetic mutations in human malignancies. Increasing evidence indicates that IDH mutations play critical roles in malignant transformation and progression. However, the therapeutic options for IDH-mutated cancers remain limited. In this study, the investigation of patient cohorts revealed that the PI3K/protein kinase B (AKT) signaling pathways were enhanced in IDH-mutated cancer cells.In this study, we investigated the gene expression profile in IDH-mutated cells using RNA sequencing after the depletion of AKT. Gene set enrichment analysis (GSEA) and pathway enrichment analysis were used to discover altered molecular pathways due to AKT depletion. We further investigated the therapeutic effect of the AKT inhibitor, ipatasertib (Ipa), combined with temozolomide (TMZ) in cell lines and preclinical animal models.GSEA and pathway enrichment analysis indicated that the PI3K/AKT pathway significantly correlated with Nrf2-guided gene expression and ferroptosis-related pathways. Mechanistically, AKT suppresses the activity of GSK3β and stabilizes Nrf2. Moreover, inhibition of AKT activity with Ipa synergizes with the genotoxic agent TMZ, leading to overwhelming ferroptotic cell death in IDH-mutated cancer cells. The preclinical animal model confirmed that combining Ipa and TMZ treatment prolonged survival.Our findings highlighted AKT/Nrf2 pathways as a potential synthetic lethality target for IDH-mutated cancers.
Mpox virus and transmission through sexual contact: Defining the research agenda
Authors: Nicola Low, Laura H. Bachmann, Dimie Ogoina, Robert McDonald, Aziz Mert Ipekci, Laura A. S. Quilter, Muge Cevik
Journal: PLoS Medicine (2023)

A multicountry outbreak of mpox (formerly monkeypox) in 2022 has affected gay, bisexual, and other men who have sex with men disproportionately, highlighting the need to understand the role of sexual contact in transmission.• While mpox virus (mpoxv) is not a novel pathogen and has been circulating in subsaharan Africa for many years, sexual transmission has not been well described.• Epidemiological, clinical, and virological data indicate that transmission of mpoxv through sexual contact, both penetrative and nonpenetrative, is more effective than transmission through casual skin-to-skin contact.• This article addresses many remaining questions about factors associated with the sexual route of mpoxv transmission and provides a framework within which research studies can be prioritised to guide policy and prevention needs.A multicountry outbreak of mpox (formerly monkeypox) was first identified in Europe in May 2022 [1].The number of new cases peaked in mid-August, followed by a rapid decline, which has continued in most affected countries.Countries with the largest numbers of cases have previously reported either no cases or sporadically imported cases from countries with endemic circulation.The outbreak has remained almost exclusively in social and sexual networks of gay, bisexual, and other men who have sex with men (GBMSM), raising many questions about the role of sexual contact in mpox virus (mpoxv) transmission.Many pathogens can be transmitted during sexual contact, mainly through genital fluids during sexual intercourse or through contact with skin or mucosal lesions.Mpox can be described as sexually transmissible, meaning that transmission can occur during a sexual encounter, with or without penetrative sexual intercourse.We do not address the question of whether mpox should be called "a sexually transmitted infection" (STI) or "a sexually transmitted disease" because those terms are inconsistently defined or applied in the literature.Understanding the role of sexual contact in
Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong
Authors: Philip C. M. Au, Kathryn C. B. Tan, David C. L. Lam, Bernard M. Y. Cheung, Ian C. K. Wong, Wang Chun Kwok, Chor-Wing Sing, Ching-Lung Cheung
Journal: JAMA Network Open (2023)

Patients with diabetes are at higher risk for obstructive airway disease (OAD). In recent meta-analyses of post hoc analyses of cardiorenal trials, sodium-glucose cotransporter 2 inhibitors (SGLT2Is) were suggested to reduce the risk of OAD adverse events. However, a clinical investigation of this association is warranted.This study aimed to investigate the association of SGLT2I use vs dipeptidyl peptidase-4 inhibitor (DPP4I) use with OAD incidence and exacerbation events in patients with type 2 diabetes.This retrospective population-based cohort study used electronic health data from a territory-wide electronic medical database in Hong Kong. Data were collected for patients with type 2 diabetes who were prescribed SGLT2Is or DPP4Is between January 1, 2015, and December 31, 2018. Patients were followed for a median of 2.2 years between January 1, 2015, and December 31, 2020. A prevalent new-user design was adopted to match patients based on previous exposure to the study drugs. Propensity score matching was used to balance baseline characteristics.Patients with type 2 diabetes using SGLT2Is (exposure of interest) or DPP4Is (active comparator).The main outcomes were the first incidence of OAD and the count of OAD exacerbations. The risk of incident OAD was estimated using a Cox proportional hazards regression model. The rate of exacerbations was estimated using zero-inflated Poisson regression. Statistical analysis was performed on November 13, 2022.This study included 30 385 patients. The propensity score-matched non-OAD cohort (incidence analysis) consisted of 5696 SGLT2I users and 22 784 DPP4I users, while the matched OAD cohort (exacerbations analysis) comprised 381 SGLT2I users and 1524 DPP4I users. At baseline, 56% of patients in the non-OAD cohort were men and the mean (SD) age was 61.2 (9.9) years; 51% of patients in the OAD cohort were men and the mean age was 62.2 (10.8) years. Compared with DPP4I use, SGLT2I use was associated with a lower risk of incident OAD (hazard ratio, 0.65 [95% CI, 0.54-0.79]; P < .001) and a lower rate of exacerbations (rate ratio, 0.54 [95% CI, 0.36-0.83]; P = .01). The associations were consistent in sex subgroup analysis.The findings of this retrospective cohort study of patients with type 2 diabetes in Hong Kong suggest that SGLT2I use was associated with a reduced risk of incident OAD and a lower rate of exacerbations in a clinical setting compared with DPP4I use. These findings further suggest that SGLT2Is may provide additional protective effects against OAD for patients with type 2 diabetes and that further investigation is warranted.
Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy and Survival of Patients With Low-Risk Nasopharyngeal Carcinoma
Authors: Timothy A. Lin, Lee-Jen Wei, Ethan B. Ludmir
Journal: JAMA (2023)

To the Editor A recent study1 assessed the noninferiority of IMRT alone vs concurrent chemoradiotherapy for treating low-risk NPC. The noninferiority claim was based on a 3-year failure-free survival rate with a noninferiority margin of 10% for the absolute failure-free survival rate difference.
Distinct early cellular kinetics in participants protected against colonization upon Bordetella pertussis challenge
Authors: Annieck M. Diks, Hans de Graaf, Cristina Teodosio, Rick J. Groenland, Bas de Mooij, Muktar Ibrahim, Alison R. Hill, Robert C. Read, Jacques J.M. van Dongen, Magdalena A. Berkowska
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDTo date, only limited data are available on the mechanisms of protection against colonization with Bordetella pertussis in humans.METHODSIn this study, the cellular responses to B. pertussis challenge were monitored longitudinally using high-dimensional EuroFlow-based flow cytometry, allowing quantitative detection of more than 250 different immune cell subsets in the blood of 15 healthy donors.RESULTSParticipants who were protected against colonization showed different early cellular responses compared with colonized participants. Especially prominent for colonization-protected participants were the early expansion of CD36- nonclassical monocytes on day 1 (D1), natural killer cells (D3), follicular T helper cells (D1-D3), and plasma cells (D3). Plasma cell expansion on D3 correlated negatively with the CFU load on D7 and D9 after challenge. Increased plasma cell maturation on D11-D14 was found in participants with seroconversion.CONCLUSIONThese early cellular immune responses following experimental infection can now be further characterized and potentially linked to an efficient mucosal immune response, preventing colonization. Ultimately, their presence may be used to evaluate whether new B. pertussis vaccine candidates are protective against B. pertussis colonization, e.g., by bacterial challenge after vaccination.TRIAL REGISTRATIONClinicalTrials.gov NCT03751514.FUNDINGInnovative Medicines Initiative 2 Joint Undertaking and the EuroFlow Consortium.
FDA Warns of Risks of Body Sculpting
Authors: Rita Rubin
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
BosR and PlzA reciprocally regulate RpoS function to sustain Borrelia burgdorferi in ticks and mammals
Authors: André A. Grassmann, Rafal Tokarz, Caroline Golino, Melissa A. McLain, Ashley M. Groshong, Justin D. Radolf, Melissa J. Caimano
Journal: Journal of Clinical Investigation (2023)

The RNA polymerase alternative σ factor RpoS in Borrelia burgdorferi (Bb), the Lyme disease pathogen, is responsible for programmatic-positive and -negative gene regulation essential for the spirochete's dual-host enzootic cycle. RpoS is expressed during tick-to-mammal transmission and throughout mammalian infection. Although the mammalian-phase RpoS regulon is well described, its counterpart during the transmission blood meal is unknown. Here, we used Bb-specific transcript enrichment by tick-borne disease capture sequencing (TBDCapSeq) to compare the transcriptomes of WT and ΔrpoS Bb in engorged nymphs and following mammalian host-adaptation within dialysis membrane chambers. TBDCapSeq revealed dramatic changes in the contours of the RpoS regulon within ticks and mammals and further confirmed that RpoS-mediated repression is specific to the mammalian-phase of Bb's enzootic cycle. We also provide evidence that RpoS-dependent gene regulation, including repression of tick-phase genes, is required for persistence in mice. Comparative transcriptomics of engineered Bb strains revealed that the Borrelia oxidative stress response regulator (BosR), a noncanonical Fur family member, and the cyclic diguanosine monophosphate (c-di-GMP) effector PlzA reciprocally regulate the function of RNA polymerase complexed with RpoS. BosR is required for RpoS-mediated transcription activation and repression in addition to its well-defined role promoting transcription of rpoS by the RNA polymerase alternative σ factor RpoN. During transmission, ligand-bound PlzA antagonizes RpoS-mediated repression, presumably acting through BosR.
New Gene Therapy for Certain Bladder Cancers
Authors: Rita Rubin
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Incorrect Term
Authors: Aidan Cashin, Benedict Wand, James Mcauley
Journal: JAMA (2023)

Although the RESOLVE trial used recommended methods for random assignment of participants to prevent selection bias, it is not guaranteed that the groups will be equivalent at baseline.Dr Jiao and colleagues correctly identify that more participants in the control group reported using weak opioids compared with the intervention group at baseline (16/ 138 [12%] vs 5/138 [4%]).Any differences in baseline characteristics, including the minimal differences in baseline pain intensity, are the result of chance 2 and not likely to have biased our trial findings.The low prevalence of opioid use reflects prescribing practices in Australian primary care. 3 In this trial, we did not record demographic data on the race or ethnicity of the participants, although we agree with Jiao and colleagues that they might be an important consideration.Greater transparency in the description of the selection and representativeness of study participants is an important methodologic feature of research 4 and requires greater recognition in low back pain research. 5Self-reported outcomes by blinded participants at follow-up (eg, pain intensity at 18, 26, and 52 weeks) reduced the potential influence of this important demographic characteristic on outcome assessment.Participants were not required to stop ongoing treatment for their low back pain while participating in our trial.This was both an ethical and pragmatic decision due to the included sham procedure and attention control and to optimize patient recruitment.We agree with Jiao and colleagues that details of the additional treatments received by participants in each group, including other physical therapy interventions, could assist with interpretations of the trial findings.There is no published guidance about how to capture and report cointerventions in clinical trials, and we agree that efforts are required to support consensus reporting of co-interventions in clinical trials. 6These data will be reported separately in trial process evaluations (eg, economic analysis).
Caution With Conclusions and Context of Mechanical Circulatory Devices
Authors: Christophe Vandenbriele, Guido Tavazzi, Susanna Price
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation
Authors: Francesca Orzan, Francesca De Bacco, Elisabetta Lazzarini, Giovanni Crisafulli, Alessandra Gasparini, Angelo Dipasquale, Ludovic Barault, Marco Macagno, Pasquale Persico, Federico Pessina, Beatrice Bono, Laura Giordano, Pietro Zeppa, Antonio Melcarne, Paola Cassoni, Diego Garbossa, Armando Santoro, Paolo M. Comoglio, Stefano Indraccolo, Matteo Simonelli, Carla Boccaccio
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas. Experimental Design: We recruited two cohorts of newly diagnosed patients with glioma, one (n = 45) providing CSF collected in proximity of the tumor, the other (n = 39) CSF collected by lumbar puncture (LP). Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional and molecular diagnosis outcomes were compared. Results: We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from LP. Indeed, tumor DNA is mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in &amp;gt;60% of LP CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes. Conclusions: This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.
How Was Clinic?
Authors: Matthew J. Farrell
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Engineering mighty microglia
Authors: Adeline E. Walsh, John R. Lukens
Journal: The Journal of Experimental Medicine (2023)

Defective microglial responses underlie many neurological disorders. Recent efforts to swap out dysfunctional microglia with optimized replacements have been derailed by safety issues and transplantation inefficiencies. In this issue, Chadarevian et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20220857) designed a novel strategy that enables improved engraftment of human microglia.
Improving Orthologous Signal and Model Fit in Datasets Addressing the Root of the Animal Phylogeny
Authors: Charley G P McCarthy, Peter O Mulhair, Karen Siu-Ting, Christopher J Creevey, Mary J O’Connell
Journal: Molecular Biology and Evolution (2023)

There is conflicting evidence as to whether Porifera (sponges) or Ctenophora (comb jellies) comprise the root of the animal phylogeny. Support for either a Porifera-sister or Ctenophore-sister tree has been extensively examined in the context of model selection, taxon sampling, and outgroup selection. The influence of dataset construction is comparatively understudied. We re-examine five animal phylogeny datasets that have supported either root hypothesis using an approach designed to enrich orthologous signal in phylogenomic datasets. We find that many component orthogroups in animal datasets fail to recover major lineages as monophyletic with the exception of Ctenophora, regardless of the supported root. Enriching these datasets to retain orthogroups recovering ≥3 major lineages reduces dataset size by up to 50% while retaining underlying phylogenetic information and taxon sampling. Site-heterogeneous phylogenomic analysis of these enriched datasets recovers both Porifera-sister and Ctenophora-sister positions, even with additional constraints on outgroup sampling. Two datasets which previously supported Ctenophora-sister support Porifera-sister upon enrichment. All enriched datasets display improved model fitness under posterior predictive analysis. While not conclusively rooting animals at either Porifera or Ctenophora, we do see an increase in signal for Porifera-sister and a decrease in signal for Ctenophore-sister when data are filtered for orthologous signal. Our results indicate that dataset size and construction as well as model fit influence animal root inference.